Inter-rater reliability of phenotypes and exploratory genotype-phenotype analysis in inherited hidradenitis suppurativa.

BACKGROUND: Genotype-phenotype correlation measures the correlation between the presence of a physical trait with a group of similar mutations but is dependent on reliable phenotyping. It can provide information on disease pathogenesis, future disease progression, severity or activity. Such indicators would be valuable in hidradenitis suppurativa (HS). OBJECTIVES: To assess inter-rater reliability (IRR) of HS clinical phenotypes and perform exploratory genotype-phenotype correlation in cases of HS with identified sequence variants. METHODS: Linkage disequilibrium between variants was assessed. Genotype-phenotype correlations were explored using Spearman correlation coefficients. IRR was calculated using Cohen's κ. Correlation between phenotype classifications was assessed using the χ2 statistic. RESULTS: Forty-three sequence variants with clinical information were identified. Clinical phenotypes were classified as LC2 (n = 29; 67%), scarring folliculitis (n = 18; 42%), atypical (n = 38; 88%) and nodular (n = 26; 60%). LC1 phenotype was associated with regular (χ2 = 41·289, P < 0·001) and typical (χ2 = 29·013, P < 0·001) phenotypes. Cohen's κ was highest for van der Zee and Jemec (0·815), followed by Martorell-Calatayud et al. (0·813), Naasan and Affleck (0·774) and Canoui-Poitrine et al. (0·435) classifications. High linkage disequilibrium was seen between variants of Han Chinese pedigrees. No significant genotype-phenotype correlations were identified. CONCLUSIONS: These findings may be influenced by selection, publication bias and the assumption that HS is a monogenic disorder. The poor IRR of existing phenotype measures suggests limited utility of existing measures. Further investigations into the correlation of clinical phenotypes with inflammatory biomarkers may aid in prognostic efforts for this disease. What's already known about this topic? Genotype-phenotype correlation can provide information regarding disease pathogenesis and predictions for future disease progression, severity or activity. The identification of such indicators in hidradenitis suppurativa (HS) would be valuable for patients and clinicians alike, given the lack of biomarkers or clinical predictors of disease. What does this study add? Sixty-five sequence variants across 20 separate genes were identified. There was no significant correlation between phenotype classification in four separate classification schema and gene, mutation type or impact on Notch signalling. Utility of current phenotype measurements are limited. The lack of genotype-phenotype correlation in HS is suggestive that the underlying assumption of inherited HS as a monogenic disorder may need revision.

Passage of immunoglobulins from plasma to the oral cavity in rhesus monkeys.

The passage of immunoglobulin from plasma to the oral cavity was studied in rhesus monkeys. Immunoglobulins G, A and M were purified from pooled rhesus monkey serum, radiolabelled with 125I and injected intravenously into twelve monkeys. Sequential samples of oral fluids were taken over a 24 h period and were assayed for radioactivity. Radioactivity could be detected in crevicular fluid washings after 0.5 h in monkeys injected with IgG and IgA, and after 2 h in monkeys given IgM. Maximal levels were found after 4 h with each immunoglobulin. Radioactivity in parotid and mixed saliva could be detected in all animals after 30 min, reaching a maximal level after 4 h. Ultracentrifugation on sucrose density gradients revealed that most of the radioactivity in crevicular fluid washings was in the 7S zone in the animals given IgG and IgA, and in a 19S zone in animals given IgM. The radioactivity in partoid saliva did not represent intact immunoglobulin molecules, since all the activity was present in zones of low molecular weight in animals given IgG, IgA or IgM. In mixed saliva a small amount of radioactivity was found in the immunoglobulin zones. The results suggest that intact molecules of IgG, IgA and IgM can pass from plasma to the oral cavity via crevicular fluid, and could contribute to oral defence mechanisms particularly in the crevicular domain. The volume of crevicular fluid in the approximal space of deciduous molars of rhesus monkeys was estimated to be approximately 0.3 microliter.

Passive immunisation with serum and immunoglobulins against dental caries in rhesus monkeys.

Active immunisation with Streptococcus mutans induced protection against dental caries in rhesus monkeys, and this was associated with serum antibodies. Passive transfer of immune serum with IgG, IgM, and IgA antibodies to Strep. mutans failed to induce protection against dental caries. However, when separated IgG, IgM, and IgA sera were given, IgG induced significant protection but IgA or IgM antibodies to Strep. mutans did not. IgA and IgM may compete or interfere with the protective effect of IgG antibodies, and the ratio of IgG/IgA and IgG/IgM antibodies might be an important factor in immunisation against dental caries.

Passive immunization with antisera to Streptococcus mutans in the prevention of caries in rhesus monkeys.

1) The immunological mechanism of protection against dental caries has been investigated by passive immunization with antisera to S. mutans in the rhesus monkey. 2) Passive immunization with separated IgG, IgM and IgA from sera of immunized monkeys supports the concept that IgG, unlike IgA or IgM antibodies are protective. 3) The role of cell-mediated immunity has been explored by the use of transfer factor. This showed that protection against dental caries can be elicited by passive transfer of whole immune serum and cellular immunity, but not by cellular immunity or immune serum alone. 4) The results of active and passive immunization suggests that immuno-regulation of T and B cell interactions plays an important part in the effector mechanism of opsonization, phagocytosis and killing of S. mutans.